HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression

Misregulation of the canonical Wnt/beta-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer (CRC) and contribute to cancer progression. Altered expression of human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and CRC. However, the regulation of HEF1 and the role of HEF1 in CRC tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was upregulated by Wnt-3a, beta-catenin, and Dvl2 in a dose-dependent manner, and was suppressed following beta-catenin downregulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in CRC cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apc(Min/+) mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and promoter analyses revealed three functional T-cell factor (TCF)-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while downregulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/beta-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in CRC. Oncogene (2011) 30, 2633-2643; doi:10.1038/onc.2010.632; published online 14 February 2011